Associative factors for atopic dermatitis and other atopic diseases in middle‐aged adults: A population‐based birth cohort study among 5373 subjects

Abstract Background and aims The study aimed to examine parental, longitudinal and current associative factors for atopic dermatitis (AD) and to compare those to other atopic diseases in 46‐year‐old adults. Methods Questionnaire data from the Northern Finland Birth Cohort 1966 study were used. To analyze allergic sensitization, skin prick tests (n = 5373) were performed for birch, timothy, cat, and house dust mite at age 46. Results Maternal (odds ratio [OR] 1.81; 95% confidence interval [CI] 1.25–2.59) and paternal allergy (OR 2.54; CI 1.76–3.64), sensitization to any of the four tested aeroallergens (OR 1.56; CI 1.04–2.30) as well as polysensitization (OR 3.04; CI 2.10–4.37) were associated with current AD. Living on a farm in infancy was negatively associated with allergic rhinitis, allergic conjunctivitis, and atopic multimorbidity. Current AD (OR 2.65; CI 1.44–4.60) and all atopic diseases associated with indoor air related symptoms. Current AD associated with other atopic diseases, most strongly with allergic rhinitis (OR 4.92; CI 3.92–6.22). Conclusion Current AD in a 46‐year‐old general population occurred frequently with allergic rhinitis, allergic conjunctivitis, and asthma in the Northern Finland Birth Cohort study 1966. Parental allergy and sensitization to common aeroallergens were found as shared associative factors for AD, allergic rhinitis, allergic conjunctivitis, and asthma. AD and other atopic diseases associated with symptoms related to poor indoor air quality. In daily practice, it is important to take these comorbidities into consideration when treating patients with AD.


| INTRODUCTION
Atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), and asthma are common in adults 1,2 with a significant effect on the quality of life [3][4][5] and work performance. [3][4][5] The association between asthma and AR with AD in adults is well established, but the association of AC with AD is still uncertain. 6 Although it has been suggested that other atopic diseases develop as a consequence of the epithelial barrier disruption and inflammation in AD, that is, the atopic march, 7 longitudinal studies have found that this is not usually the sequence. 8,9 Both genetic and environmental factors contribute to the risk of atopic diseases. Parental atopic diseases have shown to increase the risk of atopic morbidity in the offspring. 1,2,10 Several environmental factors that could predispose to atopic diseases in adulthood have been studied and some differences in risk factors between atopic diseases have been found. 10 Correspondingly, atopic sensitization is variably associated with clinical manifestations of atopic diseases 1,2,10,11 and especially polysensitization has been linked to atopic multimorbidity (two or more atopic diseases). 11,12 A few studies have investigated the risk factors in AD alongside AR, AC and asthma in adults, and the findings vary between studies. 2,10,13 The aim in the present study was to investigate the associative factors for AD and to compare them to those of other atopic diseases (AR, AC, and asthma) in an unselected 46-year-old population, which is part of the Northern Finland Birth Cohort 1966.
In addition, we aimed to examine the atopic comorbidity in AD in middle-aged adults.

| Study population
Our study used data from the Northern Finland Birth Cohort 1966 (NFBC 1966), which is a longitudinal research program in the two northernmost provinces in Finland. Initially, all 12,058 children whose expected date of birth fell in the year 1966 were included in the NFBC 1966. Health questionnaires and clinical examinations have been conducted regularly on the whole cohort since birth. 14 2.2 | Skin prick test (SPT), questionnaire, and confounding factors SPT were performed at age 46 and the procedure has been described in detail in a previous article. 15 Data on atopic diseases (AD, AR, AC, and asthma) and medications for AD and asthma were collected by way of a health questionnaire at age 46. "Current AD" was defined as symptoms of AD ("Have you had a rash that has been called AD, milk crust, or dermatitis of the skin folds?") in the previous 12 months or doctor-diagnosed AD and topical corticosteroids or calcineurin inhibitors as current medication. "Lifetime AD" was defined as symptoms of AD in the previous 12 months or earlier or doctor-diagnosed AD and topical corticosteroids or calcineurin inhibitors as current medication. The definition of "asthma" included symptoms of asthma ("Have you had symptoms of asthma?") in the previous 12 months or doctor-diagnosed asthma or if inhaled corticosteroids and/or bronchodilators were reported as current medication. Symptoms of AR ("Have you had allergic rhinitis related to animals or pollens or hay fever?") and AC ("Have you had allergic eye symptoms, such as itch or watering eyes in contact with animals or during the pollen season?") in the previous 12 months or doctor-made diagnosis of these diseases were defined as "AR" and "C." "Multimorbidity" was defined as two or more atopic diseases.
Data on factors (living on a farm in infancy, 10

| Statistical analysis
Means and standard deviations (SD) or proportions were calculated and presented for each variable. The statistical significance of the mean differences and proportions of categorical variables between the atopic disease groups were estimated by a Mann-Whitney U-test and a χ 2 test, respectively. Crude odds ratios (ORs) with 95% confidence intervals (CI) for atopic diseases were assessed using a binary logistic regression model. Adjusted ORs were calculated using a binary logistic regression model, and all above-mentioned potential confounding factors were entered in the model as potential predictors for atopic diseases. All significance tests were two-tailed, and values of p < 0.05 were considered statistically significant. The statistical analyses were conducted using the R software package

| Characteristics of the study population
At 46 years, invitations and questionnaires were sent to every living member of the cohort whose address was known (n = 10,321); 5861 participants attended the clinical examination. SPTs were performed in 5714 (55.4% of invited) participants. Because of invalid data, 331 participants were excluded from the analysis, and 10 participants did not give their consent to data processing. Complete SPT data on all allergens were available for 5373 participants (2394 [44.6%] were men) who comprised the final study population. 15 Due to incompletely filled questionnaires, the study population varies by question.
The characteristics of the study population stratified by sex are shown in Table 1. 3.2 | Prevalence of atopic diseases and atopic multimorbidity at age 46 Any current atopic disease was reported by 2101 participants (39.1%). Current AD, lifetime AD, AR, AC, asthma, and multimorbidity T A B L E 1 Characteristics of the study population stratified by sex All n = 5373 Men n = 2394 Women n = 2979

| Gender
In the multivariate model, female gender was associated with current   Figures 1-4).

| Smoking, pets, BMI, and education
Smoking was not associated with atopic diseases. Having pets at age 46 negatively associated with current AD (Figure 1), AC and atopic multimorbidity (Supporting Information: Figures 2 and 4), but not with asthma or AR. BMI was not associated with AD, but higher BMI was slightly associated with asthma (OR 1.03; CI 1.01-1.06) (Supporting Information: Figure 3). In turn, higher level of education was a protective factor for asthma (OR 0.53; CI 0.30-0.95) (Supporting Information: Figure 3) but was not associated with other atopic diseases.
F I G U R E Atopic predisposition, that is, allergy of parents, was significantly associated with AD, and this effect could also be seen in AR, AC, asthma, and atopic multimorbid phenotype, which is in line with previous studies. 1,2,13 Parental asthma has been a risk factor for childhood asthma in previous studies, 25 and in the present study, paternal asthma significantly associated with asthma as well.
Difference between genders in the prevalence of atopic diseases was seen as women reported significantly more often all the atopic diseases and multimorbidity. However, in the multivariate analysis, female gender associated with current and lifetime AD, AR, AC, multimorbidity, but not for asthma. In previous studies, female gender has been a risk factor for eczema, 2,26 AD, 27 and AR. 28 In asthma, the risk is greater in young boys than girls, but after puberty the risk becomes greater in women. 29 However, a recent study found that this shift might occur again during the menopause as the agerelated risk of severe asthma was higher in men than in women after the age of 45. 30 Aeroallergen sensitization and polysensitization associated with AD in the current study. In previous studies, the association between sensitization and AD in adults has varied. 2,10,13,31 A Swedish study (n = 18,087) found that any positive SPT to aeroallergens increased the risk of any eczema, 2 whereas in another Swedish study (n = 1172), atopic sensitization was not a risk factor for current eczema. 10 Raciborski and coworkers (n = 1805 adults) did not find an association between sensitization or polysensitization and AD as a single disease in their study in Poland. 31 In a Chinese study in adults (n = 2096), sensitization to any of the 9 pollen and HDM allergens was associated with both eczema and "eczema with asthma and/or hay fever." 13 In the current study, sensitization and polysensitization associated also with AR, AC, and asthma. Corresponding findings were reported in a recent Danish study (n = 52,976), in which sensitization to common inhalant allergens was a risk factor for AR, AC, and asthma. 1 Living on a farm in infancy did not protect from current or lifetime AD or asthma. However, the protective effect on AR, AC, and multimorbidity was seen in our study. A study conducted in Sweden found a protective effect of farm upbringing on lifetime eczema, but not on current eczema. 2 However, another Swedish study with the same definitions and conducted in the same area found the protective effect also on current eczema in adults. 10 In these studies, the age range was wider (16-75 years), and the definition of AD was different from the definition used in our study. Risk factors for AR, AC, and asthma were studied in adults; in a Danish study (n = 52,976), upbringing on a farm with livestock compared to other levels of urbanization had a protective effect on allergic rhino-conjunctivitis, 1 which was also seen in the current study. The protective effect of farm upbringing on the triad of AD, asthma, and AR or their different combinations was not confirmed in another setup. 32 However, in our study, living on a farm in infancy clearly protected from multimorbidity.
Current residence or current farming were not associated with atopic diseases in our study. Having pets at age 46 negatively associated with AD, AC, and atopic multimorbidity, but not with asthma or AR. This may come from the fact that those who already have atopic diseases, especially the multimorbid phenotype, might not acquire pets in adulthood as readily.
Smoking was not associated with current or lifetime AD in our study. Previous studies on the relation between AD and smoking suggest a positive association: A systematic review and meta-analysis of 86 studies with 680,176 patients (598,296 children) found that AD in both adults and children associated with active smoking and exposure to passive smoke, but not maternal smoking during pregnancy. 33 However, differences in inclusion criteria and sample sizes in addition to regional variation were found between the included studies. 33 In the present study, symptoms related to indoor air were significantly associated with AD, AR, AC, asthma, and atopic multimorbidity, as in previous studies 21, 34 : In Sweden, several indoor air factors, including humid air and mold odor in multifamily houses, associated with eczema, allergy, and asthma. 21 Recently, a study conducted in Finland found that the toxicity of wiped dust and airborne microbes in indoor air at workplace were significantly associated with multiple work-related respiratory and ocular symptoms. 22 In the same study, the toxicity of wiped dust was significantly associated with AR. This association might be bidirectional as the toxicity of indoor air might predispose to the development of atopic diseases, or individuals with atopic morbidity might be more prone to develop symptoms related to indoor air toxins or microbes.
In this cohort of middle-aged adults, 7.3% reported current AD and 25.4% reported lifetime AD. According to a cross-sectional multicenter study, approximately 4.4% of the adults in the EU and 4.9% in the United States have AD. 27 Corresponding results have been found in a Finnish study in which a skin examination performed by dermatologists found 4.6% prevalence of AD in adults in general population. 35  of current AD or current eczema vary between studies, and this must be considered when comparing the results. The chosen questions combined with the medication data in the current study were aimed to specifically include only AD and to exclude other types of eczemas that could exaggerate the true prevalence of lifetime and current AD.
In conclusion, AD had shared associative factors with AR, AC, and asthma, including parental allergy and sensitization to aeroallergens. In addition, a common association was found with indoor air related symptoms while current residence or farming were not associated with any of the atopic diseases. Women reported atopic morbidity more often than men. Differences between associative factors were also found as living on a farm in infancy did not protect from AD or asthma, but was negatively associated with AR, AC, and multimorbidity. Patients with AD commonly had atopic comorbidities and suffered from poor indoor air, which should be remembered as factors that could contribute to the exacerbation of AD when treating AD patients.

ACKNOWLEDGMENTS
We thank all cohort members and researchers who participated in the 46-year study. We also acknowledge the work of the NFBC project centre.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
NFBC data is available from the University of Oulu, Infrastructure for Population Studies. Permission to use the data can be applied for research purposes via electronic material request portal. In the use of data, the EU general data protection regulation (679/2016) and Finnish Data Protection Act are followed. The use of personal data is based on the cohort participant's written informed consent at his/her latest follow-up study, which may cause limitations to its use.
Suvi-Päivikki Sinikumpu had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.

ETHICS STATEMENT
The Ethical Committee of the Northern Ostrobothnia Hospital District approved the study ( §94/2011), which was performed according to the Helsinki Declaration of 1983. Written informed consent for scientific purposes was received from all participants.

TRANSPARENCY STATEMENT
The lead author Suvi-Päivikki Sinikumpu affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.